Repeatability of in vivo quantification of atherosclerotic carotid artery plaque components by supervised multispectral classification.

OBJECTIVE: To evaluate the agreement and scan-rescan repeatability of automated and manual plaque segmentation for the quantification of in vivo carotid artery plaque components from multi-contrast MRI. MATERIALS AND METHODS: Twenty-three patients with 30-70% stenosis underwent two 3T MR carotid vessel wall exams within a 1 month interval. T1w, T2w, PDw and TOF images were acquired around the region of maximum vessel narrowing. Manual delineation of the vessel wall and plaque components (lipid, calcification, loose matrix) by an experienced observer provided the reference standard for training and evaluation of an automated plaque classifier. Areas of different plaque components and fibrous tissue were quantified and compared between segmentation methods and scan sessions. RESULTS: In total, 304 slices from 23 patients were included in the segmentation experiment, in which 144 aligned slice pairs were available for repeatability analysis. The correlation between manual and automated segmented areas was 0.35 for lipid, 0.66 for calcification, 0.50 for loose matrix and 0.82 for fibrous tissue. For the comparison between scan sessions, the coefficient of repeatability of area measurement obtained by automated segmentation was lower than by manual delineation for lipid (9.9 vs. 17.1 mm(2)), loose matrix (13.8 vs. 21.2 mm(2)) and fibrous tissue (24.6 vs. 35.0 mm(2)), and was similar for calcification (20.0 vs. 17.6 mm(2)). CONCLUSION: Application of an automated classifier for segmentation of carotid vessel wall plaque components from in vivo MRI results in improved scan-rescan repeatability compared to manual analysis.

Prednisolone-containing liposomes accumulate in human atherosclerotic macrophages upon intravenous administration.

Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents' risk-benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP's liposomal encapsulation improved its pharmacokinetic profile in humans (n=13) as attested by an increased plasma half-life of 63h (LN-PLP 1.5mg/kg). Second, intravenously infused LN-PLP appeared in 75% of the macrophages isolated from iliofemoral plaques of patients (n=14) referred for vascular surgery in a randomized, placebo-controlled trial. LN-PLP treatment did however not reduce arterial wall permeability or inflammation in patients with atherosclerotic disease (n=30), as assessed by multimodal imaging in a subsequent randomized, placebo-controlled study. In conclusion, we successfully delivered a long-circulating nanoparticle to atherosclerotic plaque macrophages in patients, whereas prednisolone accumulation in atherosclerotic lesions had no anti-inflammatory effect. Nonetheless, the present study provides guidance for development and imaging-assisted evaluation of future nanomedicine in atherosclerosis. FROM THE CLINICAL EDITOR: In this study, the authors undertook the first clinical trial using long-circulating liposomal nanoparticle encapsulating prednisolone in patients with atherosclerosis, based on previous animal studies. Despite little evidence of anti-inflammatory effect, the results have provided a starting point for future development of nanomedicine in cardiovascular diseases.

C-reactive protein, fatal and nonfatal coronary artery disease, stroke, and peripheral artery disease in the prospective EPIC-Norfolk cohort study.

OBJECTIVE: Circulating levels of C-reactive protein (CRP) are associated with an increased risk of coronary artery disease (CAD), stroke, and peripheral artery disease (PAD). Observational and experimental evidence suggest that CRP might differentially predict fatal and nonfatal cardiovascular events. Here, we sought to determine the predictive value of CRP for fatal and nonfatal CAD, stroke, or PAD. APPROACH AND RESULTS: CRP levels were measured in 18 450 apparently healthy participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. Cox proportional hazards models were used to quantify the association between CRP levels and fatal and nonfatal CAD events, strokes, and PAD events. Bootstrapping was applied to test for significant differences between the risk of fatal and nonfatal events. During 208 485 person-years at risk, 2915 CAD events, 361 strokes, and 657 PAD events occurred. CRP was associated with fatal and nonfatal CAD events and nonfatal PAD events. When adding CRP to predictive risk models for fatal and nonfatal events corrected for known cardiovascular risk factors, the net reclassification index was 2.1% for fatal and 1.9% for nonfatal events. Multivariate adjusted hazard ratios for fatal CAD events (hazard ratio, 1.36; 95% confidence interval, 1.27-1.46) differed significantly (mean difference, 13%; 95% confidence interval, 5.1%-21.9%; P<0.001) from the multivariate adjusted hazard ratio for nonfatal CAD events (hazard ratio, 1.21; 95% confidence interval, 1.15-1.26). CONCLUSIONS: In the EPIC-Norfolk cohort, CRP was associated with fatal and nonfatal CAD events, as well as nonfatal PAD events. Adding CRP to risk stratification models resulted in a small improvement in classification for both fatal and nonfatal events. Importantly, CRP was significantly more strongly associated with fatal CAD events than with nonfatal CAD events.

Increasing spatial resolution of 3T MRI scanning improves reproducibility of carotid arterial wall dimension measurements.

OBJECTIVE: To improve carotid 3T magnetic resonance imaging (MRI) dimension measurements in patients with overt atherosclerotic carotid artery disease. MATERIALS AND METHODS: In 31 patients with advanced atherosclerotic carotid artery disease, two high resolution (0.25 × 0.25 mm(2); HR) and two routinely used low resolution (0.50 × 0.50 mm(2); LR) carotid 3T MRI scans were performed within 1 month. After manual delineation of carotid wall contours in a dedicated image analyses program in eight slices covering the atherosclerotic plaque, image reproducibility, as well as the within-reader and between-reader variability were determined. RESULTS: We found significantly higher intraclass correlation coefficients for total wall volume, mean wall area and mean wall thickness for the HR measurements (all p < 0.05). We found a significant lower signal-to-noise and contrast-to-noise ratio for the HR compared to the LR measurements. The carotid arterial wall dimension measurements of all parameters were significantly lower for the HR compared to the LR measurements. No significant differences were observed between the within-reader and between-reader reproducibility for HR versus LR measurements. CONCLUSION: Increasing the in-plane resolution improves the reproducibility of 3T MRI carotid arterial wall dimension measurements. The use of HR imaging will contribute to a reduced sample size needed in intervention trials using MRI scanning of the carotid artery as surrogate marker for atherosclerosis progression.

ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden.

AIMS: Low HDL-C is a potent risk factor for cardiovascular disease (CVD). Yet, mutations in ABCA1, a major determinant of circulating HDL-C levels, were previously not associated with CVD risk in cohort studies. To study the consequences of low plasma levels of high-density lipoprotein cholesterol (HDL-C) due to ATP-binding cassette transporter A1 (ABCA1) dysfunction for atherosclerotic vascular disease in the carotid arteries. METHODS AND RESULTS: We performed 3.0 Tesla magnetic resonance imaging (MRI) measurements of the carotid arteries in 36 carriers of high impact functional ABCA1 mutations and 36 normolipidemic controls. Carriers presented with 42% lower HDL-C levels (P < 0.001), a larger mean wall area (18.6 ± 6.0 vs. 15.8 ± 4.3 mm(2); P = 0.02), a larger mean wall thickness (0.82 ± 0.21 vs. 0.70 ± 0.14 mm; P = 0.005), and a higher normalized wall index (0.37 ± 0.06 vs. 0.33 ± 0.04; P = 0.005) compared with controls, retaining significance after adjustment for smoking, alcohol consumption, systolic blood pressure, diabetes, body mass index, history of CVD, LDL-C, and statin use (P = 0.002). CONCLUSION: Carriers of loss of function ABCA1 mutations display a larger atherosclerotic burden compared with age and sex-matched controls, implying a higher risk for CVD. Further studies are needed to elucidate the full function of ABCA1 in the protection against atherosclerosis. These data support the development of strategies to up-regulate ABCA1 in patients with established CVD.

Novel anti-inflammatory strategies in atherosclerosis.

PURPOSE OF REVIEW: Inflammation has been widely acknowledged to contribute throughout all stages of atherogenesis. However, these recent advances in our understanding have not been translated into clinical practice in which the mainstay of treatment is still lipid-targeted therapy. This review provides an overview of promising anti-inflammatory therapies in atherosclerosis, and discusses potential drawbacks and clinical benefits. RECENT FINDINGS: Immunosuppressive drugs are likely to beneficially affect atherogenesis. Several novel anti-inflammatory targets have been scrutinized, of which some have reached clinical development stage, such as cytokine targets interleukin-1 and interleukin-6, CCR2 antagonist, selective phospholipase, and leukotriene inhibitors. Novel imaging modalities such as MRI and PET-computed tomography provide valuable surrogate inflammatory endpoints for risk stratification and testing anti-inflammatory agents in cardiovascular randomized trials. SUMMARY: Anti-inflammatory therapies hold great promise in cardiovascular prevention regimens; however, atherosclerosis is a chronic disease, and systemic long-term use of anti-inflammatory agents carries the risk of complications arising from immunosuppression. In order to successfully add immunosuppressive drugs to our routine armament, we need to identify high-risk patients who benefit from anti-inflammatory treatment, increase our insight into the inflammatory pathogenesis of atherogenesis, and find safe and effective compounds capable of directly suppressing plaque inflammation.

Chemokine ligand 2 genetic variants, serum monocyte chemoattractant protein-1 levels, and the risk of coronary artery disease.

OBJECTIVE: In humans, evidence about the association between levels of monocyte chemoattractant protein-1 (MCP-1), its coding gene chemokine (C-C motif) ligand 2 (CCL2), and risk of coronary artery disease (CAD) is contradictory. METHODS AND RESULTS: We performed a nested case-control study in the prospective EPIC-Norfolk cohort investigating the relationship between CCL2 single-nucleotide polymorphisms (SNPs), MCP-1 concentrations, and the risk of future CAD. Cases (n=1138) were apparently healthy men and women aged 45 to 79 years who developed fatal or nonfatal CAD during a mean follow-up of 6 years. Controls (n=2237) were matched by age, sex, and enrollment time. Using linear regression analysis no association between CCL2 SNPs and MCP-1 serum concentrations became apparent, nor did we find a significant association between MCP-1 serum levels and risk of future CAD. Finally, Cox regression analysis showed no significant association between CCL2 SNPs and the future CAD risk. In addition, we did not find any robust associations between the CCL2 haplotypes and MCP-1 serum concentration or future CAD risk. CONCLUSIONS: Our data do not support previous publications indicating that MCP-1 is involved in the pathogenesis of CAD.

Reduction of monocyte chemoattractant protein 1 and macrophage migration inhibitory factor by a polyphenol-rich extract in subjects with clustered cardiometabolic risk factors.

Inflammation is a hallmark of the metabolic syndrome, which also contributes to a pro-atherogenic state. NF-κB activation, a critical step in regulating inflammatory reactions, can be inhibited by polyphenol (PF) extracts, at least in vitro. In the present study, we set out to study whether a PF-rich extract could attenuate the chronic inflammatory state and/or an acute immune response in vivo in subjects with clustered metabolic risk factors. A commercially available, PF-rich extract (500 mg daily) or placebo was administered for 4 weeks to thirty-four subjects with two or more metabolic risk factors using a randomised, double-blind, cross-over design. During the final study visit, an acute inflammatory challenge (lipopolysaccharide (LPS) 1 ng/kg body weight) was administered to a random subgroup of subjects (PF-rich extract (n 12) and placebo (n 12)). The PF-rich extract modestly reduced the inflammatory chemokines monocyte chemoattractant protein 1 (MCP-1) and macrophage migration inhibitory factor (MIF) (MCP-1 - 6.5 % (PF, median 116 (interquartile range 97-136) pg/ml v. placebo, median 124 (interquartile range 105-153) pg/ml; P < 0.05); MIF - 10.8 % (PF, median 2512 (interquartile range 1898-3972) pg/ml v. placebo, median 2814.5 (interquartile range 2296-3852) pg/ml; P < 0.05); however, other measured markers of inflammation and cardiometabolic disease, such as C-reactive protein, IL-6, HDL-cholesterol, adiponectin and oxidised LDL, remained unaffected. Following the LPS challenge, we found a statistically significant 48 % reduction of MCP-1 production in the PF-rich extract group (n 12) v. placebo (n 12) over 6 h (PF 766 (sd 155) v. placebo 1466 (sd 989) ng/ml; P < 0.05, area under the curve). In conclusion, short-term oral administration of the PF-rich extract caused a modest anti-inflammatory effect in subjects with clustered metabolic risk factors. Further dose-ranging studies are needed to evaluate whether and to what extent PF-rich extracts can be used to reduce the pro-inflammatory state in subjects with metabolic diseases at increased cardiovascular risk.

Coronary Flow Assessment Using Accelerated 4D Flow MRI With Respiratory Motion Correction.

Magnetic resonance imaging (MRI) can potentially be used for non-invasive screening of patients with stable angina pectoris to identify probable obstructive coronary artery disease. MRI-based coronary blood flow quantification has to date only been performed in a 2D fashion, limiting its clinical applicability. In this study, we propose a framework for coronary blood flow quantification using accelerated 4D flow MRI with respiratory motion correction and compressed sensing image reconstruction. We investigate its feasibility and repeatability in healthy subjects at rest. Fourteen healthy subjects received 8 times-accelerated 4D flow MRI covering the left coronary artery (LCA) with an isotropic spatial resolution of 1.0 mm3. Respiratory motion correction was performed based on 1) lung-liver navigator signal, 2) real-time monitoring of foot-head motion of the liver and LCA by a separate acquisition, and 3) rigid image registration to correct for anterior-posterior motion. Time-averaged diastolic LCA flow was determined, as well as time-averaged diastolic maximal velocity (VMAX) and diastolic peak velocity (VPEAK). 2D flow MRI scans of the LCA were acquired for reference. Scan-rescan repeatability and agreement between 4D flow MRI and 2D flow MRI were assessed in terms of concordance correlation coefficient (CCC) and coefficient of variation (CV). The protocol resulted in good visibility of the LCA in 11 out of 14 subjects (six female, five male, aged 28 ± 4 years). The other 3 subjects were excluded from analysis. Time-averaged diastolic LCA flow measured by 4D flow MRI was 1.30 ± 0.39 ml/s and demonstrated good scan-rescan repeatability (CCC/CV = 0.79/20.4%). Time-averaged diastolic VMAX (17.2 ± 3.0 cm/s) and diastolic VPEAK (24.4 ± 6.5 cm/s) demonstrated moderate repeatability (CCC/CV = 0.52/19.0% and 0.68/23.0%, respectively). 4D flow- and 2D flow-based diastolic LCA flow agreed well (CCC/CV = 0.75/20.1%). Agreement between 4D flow MRI and 2D flow MRI was moderate for both diastolic VMAX and VPEAK (CCC/CV = 0.68/20.3% and 0.53/27.0%, respectively). In conclusion, the proposed framework of accelerated 4D flow MRI equipped with respiratory motion correction and compressed sensing image reconstruction enables repeatable diastolic LCA flow quantification that agrees well with 2D flow MRI.

A Novel 12-Lead Electrocardiographic System for Home Use: Development and Usability Testing.

BACKGROUND: Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide. Early diagnosis is of pivotal importance for patients with cardiac arrhythmias and ischemia to minimize the consequences like strokes and myocardial infarctions. The chance of capturing signals of arrhythmias or ischemia is substantially high when a 12-lead electrocardiogram (ECG) can be recorded at the moment when a patient experiences the symptoms. However, until now, available diagnostic systems (Holter monitors and other wearable ECG sensors) have not enabled patients to record a reliable 12-lead ECG at home. OBJECTIVE: The objective of this project was to develop a user-friendly system that enables persons with cardiac complaints to record a reliable 12-lead ECG at home to improve the diagnostic process and, consequently, reduce the time between the onset of symptoms and adequate treatment. METHODS: Using an iterative design approach, ECGraph was developed. The system consists of an ECG measurement system and a mobile app, which were developed with the help of several concept tests. To evaluate the design, a prototype of the final design was built and a final technical performance test and usability test were executed. RESULTS: The ECG measurement system consists of a belt and 4 limb straps. Ten wet Ag/AgCl electrodes are placed in the belt to optimize skin-electrode contact. The product is controlled via an app on the mobile phone of the user. Once a person experiences symptoms, he or she can put on the belt and record ECGs within a few minutes. Short instructions, supported by visualizations, offer guidance during use. ECGs are sent wirelessly to the caregiver, and the designated expert can quickly interpret the results. Usability tests with the final prototype (n=6) showed that the participants were able to put on the product within 8 minutes during first-time use. However, we expect that the placement of the product can be executed faster when the user becomes more familiar with the product. Areas of improvement focus mainly on confidence during product use. In the technical performance test, a 12-lead ECG was made and reproduced 6 times. CONCLUSIONS: We developed a new 12-lead ECG system for home use. The product is expected to be more user-friendly than current hospital ECG systems and is designed to record more reliable data than current ECG systems for home use, which makes it suitable for expert interpretation. The system has great potential to be incorporated into an outpatient practice, so that arrhythmias and ischemia can be diagnosed and treated as early as possible.

C-Reactive Protein Identifies Low-Risk Metabolically Healthy Obese Persons: The European Prospective Investigation of Cancer-Norfolk Prospective Population Study.

BACKGROUND: Conflicting data exist about the cardiovascular risk of metabolically healthy obese persons. The prognostic value of C-reactive protein (CRP) in this intriguing group is unknown. We assessed the association between CRP levels and the risk of coronary heart disease (CHD) in metabolically healthy persons with abdominal obesity. METHODS AND RESULTS: In the European Prospective Investigation of Cancer-Norfolk prospective cohort, CRP levels and information on metabolic syndrome criteria were available for 7279 participants, of whom 825 (11%) developed CHD during a follow-up period of 10.9±1.8 years. There was a trend toward a higher multivariable-adjusted hazard ratio for CHD in metabolically healthy obese participants with CRP levels >2 mg/L compared with <2 mg/L (hazard ratio 1.59, 95% CI 0.97-2.62, P=0.066). Metabolically unhealthy obese participants had significantly higher CHD risk compared with metabolically healthy obese participants with CRP levels <2 mg/L (hazard ratio 1.88, 95% CI 1.20-2.94, P=0.006). Most important, we found that the risk of CHD among metabolically healthy obese persons with CRP levels <2 mg/L was comparable to that of metabolically healthy nonobese persons (hazard ratio 0.91, 95% CI 0.60-1.39, P=0.674). CONCLUSIONS: Among metabolically healthy obese persons, low CRP levels were associated with a CHD risk comparable to that of metabolically healthy nonobese persons. CRP appears to be an easy and widely available method for identifying a low-risk subpopulation among metabolically healthy obese persons.

Manual versus Automated Carotid Artery Plaque Component Segmentation in High and Lower Quality 3.0 Tesla MRI Scans.

PURPOSE: To study the interscan reproducibility of manual versus automated segmentation of carotid artery plaque components, and the agreement between both methods, in high and lower quality MRI scans. METHODS: 24 patients with 30-70% carotid artery stenosis were planned for 3T carotid MRI, followed by a rescan within 1 month. A multicontrast protocol (T1w,T2w, PDw and TOF sequences) was used. After co-registration and delineation of the lumen and outer wall, segmentation of plaque components (lipid-rich necrotic cores (LRNC) and calcifications) was performed both manually and automated. Scan quality was assessed using a visual quality scale. RESULTS: Agreement for the detection of LRNC (Cohen's kappa (k) is 0.04) and calcification (k = 0.41) between both manual and automated segmentation methods was poor. In the high-quality scans (visual quality score ≥ 3), the agreement between manual and automated segmentation increased to k = 0.55 and k = 0.58 for, respectively, the detection of LRNC and calcification larger than 1 mm2. Both manual and automated analysis showed good interscan reproducibility for the quantification of LRNC (intraclass correlation coefficient (ICC) of 0.94 and 0.80 respectively) and calcified plaque area (ICC of 0.95 and 0.77, respectively). CONCLUSION: Agreement between manual and automated segmentation of LRNC and calcifications was poor, despite a good interscan reproducibility of both methods. The agreement between both methods increased to moderate in high quality scans. These findings indicate that image quality is a critical determinant of the performance of both manual and automated segmentation of carotid artery plaque components.

Guideline treatment results in regression of atherosclerosis in type 2 diabetes mellitus.

BACKGROUND: Efficacy of guideline cardiovascular disease prevention regimens may differ between patients with or without type II diabetes mellitus. We therefore compared change in carotid artery wall dimensions in type II diabetes mellitus and non-type II diabetes mellitus patients with a history of a major cardiovascular disease event, using magnetic resonance imaging. METHODS: Thirty type II diabetes mellitus patients and 29 age- and sex-matched non-diabetes mellitus patients with a history of stroke or myocardial infarction and a carotid artery stenosis (15%-70%) were included. In all patients, treatment was according to cardiovascular risk management guidelines. At baseline and follow-up, carotid artery vessel wall dimensions were measured using 1.5 T magnetic resonance imaging. RESULTS: After 2 years of follow-up, total wall volume of the carotid artery in type II diabetes mellitus patients decreased by 9.6% (p = 0.016). In contrast, stabilization rather than regression of carotid artery wall dimensions was observed in non-diabetes mellitus patients over a 2-year period. Body mass index was identified as a predictor of total wall volume decrease. CONCLUSIONS: Guideline treatment arrests atherogenesis in non-diabetes mellitus patients and even decreases vessel wall dimensions in type II diabetes mellitus patients. Baseline body mass index predicts cardiovascular disease prevention efficacy expressed as decrease in total wall volume. These data emphasize the importance of optimal cardiovascular-prevention, particularly in diabetes patients with a high body mass index.

Increasing the Spatial Resolution of 3T Carotid MRI Has No Beneficial Effect for Plaque Component Measurement Reproducibility.

PURPOSE: Different in-plane resolutions have been used for carotid 3T MRI. We compared the reproducibility, as well as the within- and between reader variability of high and routinely used spatial resolution in scans of patients with atherosclerotic carotid artery disease. Since no consensus exists about the optimal segmentation method, we analysed all imaging data using two different segmentation methods. MATERIALS AND METHODS: In 31 patient with carotid atherosclerosis a high (0.25 × 0.25 mm2; HR) and routinely used (0.50 × 0.50 mm2; LR) spatial resolution carotid MRI scan were performed within one month. A fully blinded closed and a simultaneously open segmentation were used to quantify the lipid rich necrotic core (LRNC), calcified and loose matrix (LM) plaque area and the fibrous cap (FC) thickness. RESULTS: No significant differences were observed between scan-rescan reproducibility for HR versus LR measurements, nor did we find any significant difference between the within-reader and between-reader reproducibility. The same applies for differences between the open and closed reads. All intraclass correlation coefficients between scans and rescans for the LRNC, calcified and LM plaque area, as well as the FC thickness measurements with the open segmentation method were excellent (all above 0.75). CONCLUSIONS: Increasing the spatial resolution at the expense of the contrast-to-noise ratio does not improve carotid plaque component scan-rescan reproducibility in patients with atherosclerotic carotid disease, nor does using a different segmentation method.

Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia.

BACKGROUND: Patients with familial hypercholesterolemia (FH) are characterized by elevated atherogenic lipoprotein particles, predominantly low-density lipoprotein cholesterol (LDL-C), which is associated with accelerated atherogenesis and increased cardiovascular risk. OBJECTIVES: This study used (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) to investigate whether arterial inflammation is higher in patients with FH and, moreover, whether lipoprotein apheresis attenuates arterial wall inflammation in FH patients. METHODS: In total, 38 subjects were recruited: 24 FH patients and 14 normolipidemic controls. All subjects underwent FDG-PET imaging at baseline. Twelve FH patients who met the criteria for lipoprotein apheresis underwent apheresis procedures followed by a second FDG-PET imaging 3 days (range 1 to 4 days) after apheresis. Subsequently, the target-to-background ratio (TBR) of FDG uptake within the arterial wall was assessed. RESULTS: In FH patients, the mean arterial TBR was higher compared with healthy controls (2.12 ± 0.27 vs. 1.92 ± 0.19; p = 0.03). A significant correlation was observed between baseline arterial TBR and LDL-C (R = 0.37; p = 0.03) that remained significant after adjusting for statin use (ß = 0.001; p = 0.02) and atherosclerosis risk factors (ß = 0.001; p = 0.03). LDL-C levels were significantly reduced after lipoprotein apheresis (284 ± 118 mg/dl vs. 127 ± 50 mg/dl; p < 0.001). There was a significant reduction of arterial inflammation after lipoprotein apheresis (TBR: 2.05 ± 0.31 vs. 1.91 ± 0.33; p < 0.02). CONCLUSIONS: The arterial wall of FH patients is characterized by increased inflammation, which is markedly reduced after lipoprotein apheresis. This lends support to a causal role of apoprotein B-containing lipoproteins in arterial wall inflammation and supports the concept that lipoprotein-lowering therapies may impart anti-inflammatory effects by reducing atherogenic lipoproteins.

Reconstituted high-density lipoprotein shortens cardiac repolarization.

OBJECTIVES: We hypothesize that increasing high-density lipoprotein cholesterol (HDL-C) shortens cardiac repolarization. BACKGROUND: HDL-C is inversely associated with sudden death. The relation between HDL-C and repolarization of the heart is unexplored. METHODS: HDL-C was elevated with reconstituted high-density lipoprotein (rHDL). Cardiac repolarization was studied by recording cardiac transmembrane potentials with the patch clamp technique from isolated rabbit cardiomyocytes that were superfused with rHDL. Infusions with rHDL (40 mg/kg body weight) were performed in dyslipidemic patients and healthy volunteers. Electrocardiograms were recorded to assess cardiac repolarization before and 24 h after infusion with rHDL. RESULTS: rHDL as well as purified human apolipoprotein AI shortened repolarization of isolated rabbit cardiomyocytes by ∼25% (p < 0.05). rHDL infusion shortened the heart rate-corrected QT interval on surface electrocardiograms in all participants (p < 0.001). CONCLUSIONS: rHDL shortens cardiac repolarization. These data provide evidence for a novel mechanism of HDL infusion that may contribute to reduction of sudden cardiac death.

Improving risk stratification for cardiovascular disease.

Identifying people at high risk of cardiovascular events is the cornerstone of cardiovascular disease prevention and a major challenge for healthcare worldwide. Recently, both inflammatory and oxidative markers have been shown to improve cardiovascular risk prediction models in a wide range of patients. Here, we evaluate a recent publication investigating the value of inflammatory and oxidative markers for the prediction of cardiovascular mortality in patients with stable coronary artery disease. This study shows that the use of multiple markers may increase the predictive power of traditional risk models. The findings are discussed in the context of cardiovascular risk prediction in general.